Therapeutically active ferrihemochromogens and process of preparing them



Patented Nov. 28, 1944 CHROMOGENS PARING THEM ND raocnss F PRE- Robert D. Barnard, Columbus, Ohio, assignor to Eli Lilly and Company, Indianapolis, Ind., a corporation of Indiana No Drawing. Application March 5, 1943,

Serial No. 478,146

Claims.

My invention relates to therapeutically active ferrihemochromogens that are soluble at physiological pH, and to the process of making them. It is the object of my invention to produce ferrihemochromogens which are therapeutically active and are suitable for parenteral administra-' 1 tion.

In order to be available for parenteral administration, it is essential that the ferrihemochromogens be soluble at physiological pH-by which I mean in the range of about pH 7.0 to pH 7.8.

Ferrihemochromogens which are soluble under highly alkaline conditions but insoluble at physiological pH'have been known. But they have not been suitable for therapeutic use, because they precipitate at physiological pH; and by reason of that precipitation they cause embolic phenomena.

Ferrihemochromogens, as the term is here used, are chemical compounds of ferriheme, or of its hydroxide or salts or esters, with non-protein compounds containing nitrogen that is actively or potentially quaternary and that is quaternary in the combination with ferriheme. Ferriheme is the prosthetic nucleus of ferrihemoglobin, one of the blood pigments; and it is also the prosthetic nucleus of the oxidized form'of cellular cytochrome, of tissue catalase, and of choline esterase. It includes the porphin ring with ferric iron. Hematin is ferriheme hydroxide; and hemin is ferriheme chloride,

The ferrihemochromogens of the present application all have in common the property of being soluble at physiological pH, and all fall in the following general class:

and nicotinamide may be classified in the subgroup of pyridine-derivative components of the vitamin B: complex.

The ferrihemochromogens of the present application have a number of therapeutic uses. Among them may be mentioned the following:

1. Injection into the blood stream, to serve as an antidote for carbon monoxide poisoning.

2. Injection into the blood stream, to serve as an antidote for poisoning from hydro-acid anions of low ionic dimension. Among those anions the following may be mentioned:

' The cyanide ion The cyanamide ion The cyanate ion The thiocyanate ion .The fluoride ion The nitro ion The sulfide ion The selenide ion i;'- The azide ion 7'. The fulmin'ate ion 3. Administration parenterally or by intestinal w r apes absorption, for supplying iron in cases of iron deto ferrohemochromogens, in which the iron is ferrous iron instead of ferric iron.

17. That it is the ferrohemochromogens which act in the blood and in other tissues to combine with carbon monoxide, to produce detoxification.

c. That it is the ferrihemochromogens which act in the blood and in the other tissues to comfication.

d. That both ferrihemochromogens and ferrohemochromogens can act as suppliers of iron, or of vitamin B- The ferrihemochromogens of this invention may be prepared by the following general method:

A simple initial ferriheme substance-such as ferriheme chloride (hemin), ferriheme bromide,

' ferriheme iodide, ferriheme hydroxide (hematin), 45 or an alkyl ester of ferriheme (such as methyl ferriheme, ethyl ferriheme, propyl ferriheme, etc.), prepared by any standard method-is dissolved in a dilute alkaline solution, such as 0.1

normalKOH, or 0.1 normal NaOH solution, or 0.1 normal LiOH, or 0.2 normal NaHCOa solution; and the desired non-protein compound containing nitrogen that is actively or potentially quaternary and forms with ferriheme a compound soluble at physiologic pH, is put into the solution, either before or after the dissolving of the initial bine with the hydro-acid ions to produce detoxievery molecular equivalent of the initial ferriheme compound. Then acid is added to the solution, such for instance as hydrochloric or sulfuric acid, to lower the pH to the desired physiological value, between pH 7.0 and pH 7.8. The solution thus obtained is a desired ferrihemochromogen, in the form of the salt of the alkali metal used.

The following are examples of my process:

Example 1:- To a solution of 50 mg. of thiamin chloride dissolved in cc. of normal NaHCOa solution is added 10 mg; (about 16 millimillimols) of ierriheme chloride. The solution thus obtained is quite alkaline. To this alkaline solution is added, drop by drop, normal acetic acid to reduce the pH to about pH 7.0. A solution of thiamin ferrihemochromogen (or ierriher'ne thiamin) is ob tained, of a pH suitable for parenteral administration.

Example 2': To a solution of 30 mg. or riboflavin dissolved in 100 cc. of 0.1 normal NaHCOa solution is added 6.3 ms. (10 millimillimols) of Ierriheme chloride. The solution thus obtained is quite alkaline. To the alkaline solution thus obtained a suflicient' quantity of hydrochloric acid is added to reduce the pH to about pH 7.5.

This entire procedure with riboflavin should be carried out in the dark. A solution of the sodium salt of riboflavin ierrihemochromogen is obtained, of a pH suitable for parenteral administration.

Example 3: To a solution of about 10 mg. of pyridoxine hydrochloride in 100 cc. of 0.1 normal NaOH solution is added,6.3 mg. of terriheme chloride. Solution occurs promptly; but the solution is very alkaline. A suflicient quantity of acid is added, conveniently hydrochloric or sulfuric acid, to reduce the pH to about pH 7.2 to pH 7.7. The

resultant solution is or the sodium salt of pyridoxine ferrihemochromogem and is at a pH suitable for parenteral administration. I

' Example 4: To a solution of 6 ms. of nicotinic acid in 200 cc. of 0.1 normal KOH solution is added 12.6 mg. of ferriheme hydroxide (hematin). Solution promptly occurs, but the solution is strongly alkaline. A sufficient quantity of acid, such as lactic acid, is added to reduce the pH to about pH 7.6. This solution is of the potassium salt of nicotinic acid ferrihemochromogen; and the pH is suitable for parenteral administration.

Example 5: About 1 g. of nicotinamide is dissolved in cc. of 0.1 normal HOH solution, and 6.3 mg. of ferriheme chlorid is added. Then sufllcient hydrochloric acid is added to reduce the pH to about pH 7.6. The solution thus obtained is of the potassium salt of nicotinamide ierrihemochromogen; and the pH is suitable for parenteral administration.

In any of the preceding examples, the solution obtained may be evaporated to dryness, desirably under reduced pressure, to obtain the ferrihemochromogen product in solid form. The solid product so. produced may be administered orally in enteric capsules or tablets; so that it passes through the stomach before being exposed to any digestive juices, and is released in the intestines, whence it is absorbed.

I claim as my invention:

1. A compound of ferriheme with a vitamin component.

2. Ferriheme riboflavin.

3. Ferriheme pyridoxine.

4. Ferriheme thiamin.

5. A compound of ferrlheme with a component or the vitamin B: complex.

ROBERT D. BARNARD. 

